Received: 31 March 2018 Revised: 31 May 2018 Accepted: 1 June 2018

DOI: 10.1111/cid.12647

ORIGINAL ARTICLE

Role of vitamin C in wound healing after dental implant surgery

in patients treated with bone grafts and patients with chronic
periodontitis
Xiao Li DDS | Li Tang DDS, PhD | Yong Feng Lin DDS | Gui Fang Xie DDS

Department of Implant Dentistry, Stomatology

Hospital, Guangxi Medical University, Nanning,
Guangxi, China
Correspondence
Li Tang, Department of Implant Dentistry,
Stomatology Hospital, Guangxi Medical
University, 10 Shuangyong Rd, Nanning,
Guangxi, China.
Email: gxtangli@foxmail.com
Funding information
National Natural Science Foundation of China,
Grant/Award Number: 81460108
Abstract
Background: Postoperative wound healing is an important part of the success of the dental
implant surgery. However, in case of complex surgery or unfavorable factors, wound healing is
often unsatisfactory.
Objective: The aim of this study was to explore the effects of vitamin C supplementation in
wound healing, following the placement of dental implants with or without bone grafts and
patients with chronic periodontitis.
Methods: This randomized controlled clinical trial included 128 patients requiring dental
implants to replace missing teeth. Patients were divided into four groups, group A received den-
tal implants supported by guided bone regeneration (GBR) technique, group B received dental
implants with Bio-Oss Collagen, group C received dental implants in patients with chronic peri-
odontitis, and group D received dental implants without any bone grafting or periodontal dis-
ease. Each group was divided into an experimental subgroup, who received vitamin C, and a
control subgroup. Follow-up appointments were performed at day 3, day 7, and day 14 postsur-
gery, during which soft tissue healing and pain response scores were evaluated using the Landry
index and visual analogue scale, respectively.
Results: The experimental subgroups had significantly higher healing indices than the controls
(P < .05) at day 7 postsurgery for group B and day 14 postsurgery for groups A, B, and C. Group
D displayed no difference between the experimental and control groups at any time point. In
reference to vitamin C for pain relief, there were no statistically significant differences between
the study groups.
Conclusion: Using vitamin C supplementation improves postoperative healing following dental
implant surgery in patients with chronic periodontitis and patients treated with GBR or Bio-Oss
Collagen grafts. However, vitamin C supplementation does not decrease the postoperative pain
associated with dental implant surgery.

KEYWORDS

chronic periodontitis, dental implant, guided bone regeneration, vitamin C, wound healing

1 | I N T RO D UC T I O N Since the conference, dental implants have become increasingly popu-

Dental implants are the best treatment option for the rehabilitation of
aesthetic and functional problems that result from tooth loss.1 The
concept of osseointegration was introduced by Dr Brånemark at the
2
Toronto Conference on Osseointegration in Clinical Dentistry in 1982.
lar, improving the quality of life for patients suffering from tooth loss.3
The process of wound healing that follows dental implant surgery is
an important factor that effects the survival and clinical success of
dental implants, particularly in patients with existing periodontal dis-
ease or in patients requiring complex implant surgery.4

Clin Implant Dent Relat Res. 2018;1–6. wileyonlinelibrary.com/journal/cid © 2018 Wiley Periodicals, Inc. 1
2 LI ET AL.
Generally, the healing of a dental implant wound is spontaneous.
Clinically, many patients present with local and general factors that
can influence wound healing, such as bone loss, pathologic tooth
mobility, nutritional deficiencies, and immune deficiencies.5 Addition-
ally, wound healing may be delayed in patients who lack proper oral
hygiene, smoke or chew tobacco, and are 65 years of age or older.
For example, wound healing may be compromised in some patients
with chronic periodontal disease. Furthermore, any conditions affect-
ing the bone may compromise the surface interface between the
implant (composed of titanium, ceramics, or other alloplastic materials)
and the surrounding connective tissue.6 The process of wound healing
that follows dental implant surgery is more complex than the process
involving other oral issues.7 Currently, there is no uniform procedure
for the management of wound healing after dental implant surgery.
Vitamin C (ascorbic acid) is a water-soluble micronutrient required
for human health.8 As the body is unable to synthesize vitamin C
endogenously, humans require external sources of vitamin C from die-
tary intake and supplementation. The Food and Nutrition Board of the
National Academy of Sciences recommends a vitamin C daily intake
of 60 mg for adults,9 while the World Health Organization recom-
mends a daily intake of 45 mg. In order for the body to properly func-
tion, it has been recommended that adults should receive no less than
200 mg of vitamin C from their daily diet.10 Vitamin C deficiency, also
known as scurvy, occurs when plasma vitamin C concentrations
decrease to less than 11 μmol/L, which interferes with collagen syn-
thesis and delays wound healing in patients.11 In addition, patients
with marginal vitamin C deficiency, with plasma vitamin C concentra-
tion below 23 μmol/L, may go undiagnosed for years.12
Vitamin C is a cofactor for a large family of metalloenzymes
involved in the synthesis of collagen, neurotransmitters, and peptide
hormones, as well as the regulation of transcription factors such as
hypoxia inducible factor-1.13,14 Vitamin C especially promotes kerati-
nocyte proliferation and fibroblast migration, enhances synthesis col-
lagen, and stabilizes the collagen molecule tertiary structures; it
appears crucial for the healing/regeneration process and wound heal-
ing.15,16 In addition, vitamin C is an effective antioxidant that relieves
oxidative stress and participates in a variety of biochemical reactions.
Vitamin C is an important cofactor for several enzymatic reactions
occurring in the body, and it can promote anti-inflammatory progres-
17,18
sion through multipotent mechanisms in macrophages. Vitamin C
can decrease the responses of some inflammatory biomarkers, includ-
ing C-reactive protein, and several pro-inflammatory cytokines such
as tumor necrosis factor, interferons, and interleukins.19 In addition,
vitamin C can influence the wound-healing genes, such as inhibiting
the activation of nuclear factor kappa-light-chain-enhancer of acti-
vated B cells and endothelial cells, which play important roles in the
regulation of gene expression during inflammation.18
Therefore, vitamin C promotes wound healing through pleiotropic
mechanisms, including promoting matrix deposition and neovasculari-
zation in healing wounds and reducing the secretion of inflammatory
mediators. This article aims to investigate the role of vitamin C supple-
mentation in wound healing following dental implantation with and
without bone grafts and patients with chronic periodontitis. In addi-
tion, the effects of vitamin C supplementation on postoperative pain
have also been investigated.
2 | M A T E R I A L S A N D M ET H O D
2.1 | Study design and patient selection
In this randomized controlled clinical trial, a total of 128 adult patients
(68 females and 60 males) who required a dental implant were
selected from the Department of Dental Implants, at the Guangxi
Medical University Stomatology Hospital in Nanning, Guangxi. The
set of criteria used for patient selection is represented in Table 1. The
description of participants’ characteristics is shown in Table 2.
The study protocol was approved by the ethical committee of
Guangxi Medical University (Nanning, Guangxi). All participants signed an
informed consent to participate in this study. This clinical trial was con-
ducted in accordance with the revised Declaration of Helsinki from 2008.
2.2 | Study groups
The selected patients (n = 128) were divided into four groups, from A
to D. Group A (n = 30) received dental implants supported by the
guided bone regeneration (GBR) technique. Group B (n = 30) received
dental implants and Bio-Oss Collagen grafts. Group C (n = 32) were
patients suffering from chronic periodontitis who received dental
implants. Group D (n = 36) were patients free of periodontitis who
received dental implants without using any bone grafts.
Furthermore, each group was divided into two subgroups, includ-
ing an experimental group that received vitamin C supplements and a
control group that did not receive vitamin C. The Landry index was
used to evaluate the soft tissue healing at 3, 7, and 14 days postsur-
gery, while the visual analogue scale (VAS) was used to assess postop-
erative pain at 1, 3, and 7 days postsurgery.
2.3 | Surgical procedure
For the participants in all groups, the surgical placement of dental
implants was performed by an experienced implantologist, using local
anesthesia (Articaine, Pierre Rolland, Bordeaux, France) with a hori-
zontal releasing incision. In the case of GBR, one horizontal and two
vertical releasing incisions were used for placement of the dental
implant (Dental Nobel Biocare, Karlskoga, Sweden, and Straumann,
Basel, Switzerland).
TABLE 1 Selection criteria used for the recruitment of patients
Inclusion criteria Exclusion criteria
1. Healthy adults (18-80 years) 1. Patients with diabetes or
other systemic diseases that
can affect wound healing
2. Patients with missing teeth 2. Patients on regular medication
and requiring dental implants currently
to replace missing teeth
3. Patients with chronic 3. Pregnant women
periodontitis who already
received scaling and root
planning
4. Patients lacking cooperation
or unable to express their
feelings clearly in the routine
follow-up
LI ET AL. 3

TABLE 2 The description of participant characteristics

Groups Mean age Females Males

Group A (n = 30) 41.23 (19; 76) 13 17 Group A
Group B (n = 30) 46.00 (28; 64) 18 12
Group C (n = 32) 48.72 (29; 66) 18 14
Group D (n = 36) 43.83 (21; 68) 19 17
Group B

2.4 | Grafting procedures

After the placement of implants in patients from group A with GBR,
the inorganic bovine bone material (Princeton, New Jersey: Geistlich Group C
Bio-Oss) was placed into the buccal and lingual/palatal side of the
defect, which was covered using a single collagen membrane
(Geistlich Bio-Gide). For patients in group B, bone collagen (Geistlich
Bio-Oss Collagen) was used to fill the gap around the dental implants. Group D
Surgical sites were sutured using 4-0 Vicryl absorbable sutures
(Ethicon, New Jersey) and the patients were prescribed 0.2% chlor-
hexidine mouthwash for use after meals for 2 weeks. All patients were Control Experimental
prescribed amoxicillin (500 mg, three times a day) orally for 7 days
after surgery. Penicillin-sensitive patients were prescribed josamycin FIGURE 1 Clinical presentation of images comparing the control and
experimental subgroups in groups a-d at day 14 postoperative follow-
(500 mg, three times a day) orally after surgery, treated days same as
up [Color figure can be viewed at wileyonlinelibrary.com]
amoxicillin. In addition, patients of the experimental subgroups were
given vitamin C (300 mg/d) orally for 7 days after surgery.
At day 14 postsurgery, experimental subgroups of groups A and C
2.5 | Postoperative evaluation showed significantly improved wound healing when compared with
the control groups (P < .05). However, there were no statistically sig-
Wound healing was evaluated on days 3, 7, and 14 postsurgery using the
20 nificant differences between subgroups of groups A and C at the ear-
Landry index. Briefly, the healing tissues were clinically evaluated for
lier follow-up visits (days 3 and 7 postsurgery). In group B, although
specific features, including gingival color, response to palpation, presence
there was no significant difference at day 3 postsurgery, the experi-
of granulation tissues, and epithelialization status of the incision margin.
mental group had a higher healing index compared with the control
The evaluation was made using a healing index of 1 to 5 with 1 being very
group at days 7 and 14 postsurgery (P < .05). In group D, there were
poor, 2 as poor, 3 as good, 4 as very good, and 5 representing excellent
no statistically significant differences between the subgroups at any
healing. The pain assessment was performed using VAS at the follow-up
visits, using a nongraded straight line of 100 mm, with the leftmost “0” time intervals. In groups A, B, and C, healing was improved with the

representing no pain and right “10” representing the worst possible pain. 21 increase of treatment time (Table 4).

2.6 | Statistical analysis 3.2 | Effects of vitamin C on postoperative pain

The data were analyzed using the SPSS software (version 20.0, Armonk, Vitamin C showed no postoperative pain relief properties in this

New York: IBM). The Mann-Whitney U test was used to compare differ- study, as there were no statistically significant differences between

ences in each group. The generalized estimating equations were used to the vitamin C and control subgroups in groups in A, B, C, or D

compare the effects of vitamin C on wound healing over time. A P value (Table 5).
of less than .05 (P < .05) was considered statistically significant.
TABLE 3 Wound healing scores compared among groups at day
14 follow-up
3 | RESULTS
Group Type of intervention Mean  SD P value
Group A Experimental subgroup (n = 15) 4.87  0.35 <.0001
3.1 | Wound healing Control subgroup (n = 15) 3.93  0.46

All dental implants osseointegrated successfully and there were no Group B Experimental subgroup (n = 15) 4.80  0.41 <.0001

reported clinical complications during the follow-up period. The post- Control subgroup (n = 15) 4.07  0.26

operative wound healing response of gingival tissues from representa- Group C Experimental subgroup (n = 17) 4.76  0.44 .002
Control subgroup (n = 15) 4.00  0.66
tive patients of each groups was compared (Figure 1).
Group D Experimental subgroup (n = 18) 4.67  0.49 .791
Wound healing scores have been compared among the study
Control subgroup (n = 18) 4.61  0.50
groups at the follow-up on day 14 postsurgery (Table 3). (The data for
the third and seventh postsurgery days have not been included.) Landry index; Mann-Whitney U test
4 LI ET AL.

TABLE 4 Comparison of the effect of vitamin C in wound healing promotes cell division and secretion of matrix proteins. VEGF also
postsurgery on groups a-d promotes angiogenesis, which is an essential element for the regener-
Group Variable Wald χ2 P value ation of damaged tissues.24,28 Finally, vitamin C has been shown to
Group A Subgroups 11.18 .001 promote wound healing in both small animal studies29 and human
Time 43.32 <.0001 trials.15,30
Group B Subgroups 14.35 <.0001 In the current study, vitamin C played a significant role in increas-
Time 26.99 <.0001 ing wound healing by day 14 postsurgery in patients with chronic
Group C Subgroups 5.97 .015 periodontitis and patients treated with GBR. Additionally, wound heal-
Time 25.65 <.0001 ing was comparatively better by day 7 postsurgery in patients treated
Group D Subgroups 0.06 .807 with the Bio-Oss Collagen. However, wound healing did not improve
Time 39.23 <.0001 in any of the experimental groups by day 3 postsurgery.
Landry index; Generalized estimating equations; subgroups(experimental Vitamin C is a cofactor involved in the hydroxylation of type IV
and control group.): groups a, b, and c, P < .05, statistically significant dif- collagen and facilitation of oxidative protein folding, further leading to
ference between groups; group d, P > .05, no statistically significant differ-
ence between groups; Time(day 3,7 and 14): P < .05, the time difference the maturation of collagen.31 Therefore, we speculate that wound
was statistically significant. healing is disturbed when plasma concentrations of vitamin C reach
low levels. Reductions in plasma vitamin C concentration may be
4 | DISCUSSION caused by malnutrition, trauma, and surgery.32 While vitamin C con-
centrations were not evaluated in patients after surgery, we predict
The current study explored the effects of vitamin C in wound healing that the levels dropped as a result of the trauma resulting from the
following the placement of dental implants with and without bone surgery. In group D, participants did not accompany periodontitis or
grafts. The primary outcome of this clinical trial was that postopera- underwent complex operative procedures such as GBR. In other
tive administration of vitamin C improved the healing potential in words, there was a little trauma and no foreign body (bone graft mate-
patients suffering from chronic periodontitis and patients treated with rial or biofilm) reaction or diseases that may affect postoperative
GBR or Bio-Oss Collagen grafts. However, the use of vitamin C sup- wound healing (chronic periodontitis). Therefore, the control subgroup
plementation did not reduce the postoperative pain associated with of group D has markedly higher wound healing scores compared to
dental implant surgery. The role of nutrients and vitamins for peri- other three groups.
odontal health and wound healing has been extensively investigated However, vitamin C supplementation showed no benefits in
in other studies.22,23 patients treated with dental implants alone. This may be attributed to
The wound healing process is typically composed of three con- the varying severity of trauma among these patients, which likely
secutive and overlapping stages, including inflammation, new tissue resulted in large differences in plasma vitamin C concentration
formation, and remodeling.24 In addition, the healing process involves between the patients in group D. Also, the dosage of vitamin C
a cascade of events, such as blood clot formation, neutrophil adhe- (300 mg/d) prescribed may have been too low to produce a therapeu-
sion, and formation of granulation tissue, which is followed by con- tic response in these patients. In contrast, intravenous administration
nective tissue reepithelialization and the formation of mature of vitamin C may have yielded plasma vitamin C concentrations
tissues.25,26 The healing process for oral wounds closely mimics the approximately 250-times higher than that of patients receiving vita-
wound healing of other connective tissues in the body.27 Therefore, min C supplements orally.33 Lastly, the individual plasma vitamin C
there are three primary factors involved in wound healing, including concentration of each patient may have affected the results of this
angiogenesis, immune response, and epithelialization.24,28 Previously, study. The surgical procedure conducted in patients from group D
Mohammed and colleagues18 showed that vitamin C could promote was less invasive than the procedure performed in the other groups,
wound healing through a variety of mechanisms. For example, vitamin which suggests that group D plasma vitamin C levels may have been
C protects the function of vascular endothelium, increasing the affected less by the surgery. While baseline vitamin C levels may have
expression of vascular endothelial growth factor (VEGF), which a general impact on patient health, supplemental vitamin C is essential

TABLE 5 Assessment of pain scores in the four groups

Group Type of intervention Day 1 Day 3 Day 7

Group A Experimental subgroup (n = 15) 4.47  1.12 1.81  1.37 0.18  0.36
Control subgroup (n = 15) 5.38 1.00 2.77 1.29 0.67  0.77
Group B Experimental subgroup (n = 15) 4.45  1.57 1.66  1.19 0.07  0.26
Control subgroup (n = 15) 4.47  1.61 2.18  1.53 0.53  0.85
Group C Experimental subgroup (n = 17) 4.22  1.92 1.59  1.03 0.19  0.32
Control subgroup (n = 15) 4.80  2.23 2.07  1.83 0.87  0.95
Group D Experimental subgroup (n = 18) 4.51  1.45 1.99  1.41 0.22  0.59
Control subgroup (n = 18) 4.30  1.29 1.55  1.04 0.14  0.29

visual analogue scale (VAS); No statistically significant differences were observed; Mann-Whitney U test; P > .05.
LI ET AL.
for improving wound healing.34 Conversely, the administration of
high-dose vitamin C may cause adverse effects, including kidney
stones and cardiovascular diseases, in some patients.35,36
Compared to experiments in mice evaluated at 7 days postsur-
gery, the vitamin C-enriched experimental group showed an obvious
increase in collagen deposition and the formation of dense granulation
tissue.18 In this study, the effects on wound healing became visible by
day 14 postsurgery. Some reasons for this difference include varia-
tions in plasma vitamin C levels, the degree of surgical trauma, and the
dosage of vitamin C given to patients. In patients with chronic peri-
odontitis (group C), bacterial infections could lead to marginal vitamin
C deficiency.
Vitamin C is transported from the plasma to gingival tissues
through the sodium-dependent vitamin C transporter 1 (SVCT1).37
SVCT1 is a high-capacity and low-affinity transporter (Km = 65-237
μmol/L) that mediates the uptake of vitamin C from the diet. 38
How-
ever, SVCT1 does not function at low concentrations of vitamin C,
meaning that it is critical to define the optimal dosage of vitamin C
required for effective wound healing in patients.
While previous studies have reported a direct correlation
between vitamin C and pain control, 39,40
the current study suggests
that vitamin C has minimal effect on postoperative pain after dental
implant surgery. Again, this could have been as a result of the low dos-
age of vitamin C used in this clinical trial (300 mg/d), as the other
studies used higher oral dosages (>300 mg/d) or very high dosages
(>10 g) given via intravenous injection, but only twice a week. 40
Addi-
tionally, pain is an individual and subjective experience that is associ-
ated with a variety of factors. Therefore, the quantitative pain
measurement may vary among patients from different ethnicities.
Healing of an implant wound is a complex process likely affected
by multiple factors and individual variations. For instance, functional
masticatory stresses from the tooth (crown or bridge) adjacent to the
dental implant may jeopardize the healing, when compared to the
41
wound healing of a surgical site without an adjacent prosthesis.
There were a few limitations of this clinical trial. First, it was diffi-
cult to control the social element lifestyle of patients. For instance,
certain patients may be consuming significant amounts of vitamin C
from their normal diet, while other patients may have a lower intake
of daily vitamin C. As we did not record the daily diet patterns of
patients, this could have affected the outcome of the study. Similarly,
individual plasma vitamin C concentrations were not recorded for the
patients. In addition, patients with other social behaviors, such as alco-
holics and smokers, were neither excluded nor controlled in this study,
despite smoking and alcohol being two factors known to affect wound
healing times.28,42
Furthermore, smoking is likely to affect the turnover of vitamin C,
as smoking diminish the intake and consumption of vitamin
C. Nonsmokers have shown to consume 50%-75% more vitamin C
compared to smokers.43 In addition, vitamin C can partially restore the
damage caused by smoking, including the chemotaxis activity of
monocytes.44 This is important because monocytes are a primary
source of growth factors that play an essential role in the vascular
remodeling that occurs during wound healing. In the study, vitamin C
supplementation in smokers (n = 8) resulted in improved healing
5
potential. However, the authors could not establish any statistical sig-
nificance because of the small sample size.
Considering the positive effects that vitamin C have on improving
wound healing, we recommend that vitamin C be given to patients
prior to implantation to increase plasma vitamin C levels and improve
postoperative responses. There are no reported adverse effects asso-
ciated with the use of vitamin C supplements, when used in the
recommended dosage range. However, further studies are needed to
assess the optimal route of administration and dosage needed to
improve wound healing in patients undergoing dental implant surgery.
5 | CONC LU SION
Vitamin C supplementation improves postoperative wound healing
following dental implant surgery in patients with chronic periodontitis
and in patients treated with GBR or Bio-Oss Collagen grafts. How-
ever, vitamin C supplementation was ineffective in decreasing the
postoperative pain associated with dental implant surgery. While vita-
min C supplementation may play an important role in postsurgical
wound healing, the individual variations between patients and factors
like patient lifestyle, age, and drug use may affect the outcome.
ACKNOWLEDGMENT
This study was supported from the National Natural Science Founda-
tion of China (Grant 81460108).
CONFLIC T OF INT E RE ST
The authors declare that they have no conflicts of interest.
ORCID
Xiao Li http://orcid.org/0000-0002-6609-5140
Li Tang http://orcid.org/0000-0001-5468-985X
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How to cite this article: Li X, Tang L, Lin YF, Xie GF. Role of
vitamin C in wound healing after dental implant surgery in
patients treated with bone grafts and patients with chronic
periodontitis. Clin Implant Dent Relat Res. 2018;1–6. https://
doi.org/10.1111/cid.12647